Void nucleation and disentanglement in glassy amorphous polymers.
Cavitation in glassy polymers is known to result from highly triaxial states of local stress and the presence of impurities. Understanding of cavitation, particularly void nucleation, is important as cavities are precursors to crazes, which in turn lead to fracture. In this work we study the early stages of void nucleation in glassy amorphous polymers by imposing, in well designed molecular dynamics simulations, highly triaxial states of stress on ensembles of entangled linear macromolecular chains and monitoring the evolution of the entanglement network. Our results demonstrate that deformation induced disentanglement and rearrangement of topological constraints along individual chains play an important role in the early stages of void nucleation. Even in the glassy state, deformation causes significant changes in the rheological constraints on a chain though the number of interchain binary contacts may not change much.


Contribution of Palmar Radiocarpal and Ulnocarpal Ligaments to the Stability of the Canine Antebrachiocarpal Joint.
The aim of this study was to evaluate the contribution of the palmar radiocarpal ligament and the palmar ulnocarpal ligament to canine antebrachiocarpal joint stability. The right carpus of four dog cadavers, free of musculoskeletal pathology, was stripped of muscle. Each specimen was placed into a custom-made joint testing machine and tested at 15° extension, and 0° and 15° flexion. A single motion tracking sensor was fixed to the metacarpal bones. All specimens were tested with all ligaments intact and after transection of the palmar radiocarpal and ulnocarpal ligaments. A range of weights between 0.2 and 2.0 kg was used to test the carpi in three directions (axial, medial/lateral and cranial/caudal) and two moments (pronation/supination and valgus/varus). No differences were found between the translations and rotations of the manus relative to the radius and ulna with the ligaments intact and the ligaments transected at any of the carpal angles tested, except at 15° of flexion. Increasing the angle of flexion resulted in a significant increase in cranial and caudal translation of the manus relative to the radius and ulna both in the intact and transected specimens. Antebrachiocarpal joint position plays a more important role in craniocaudal antebrachiocarpal joint stability than the palmar radiocarpal and ulnocarpal ligaments.


Investigation of WO3 Electrodeposition Leading to Nanostructured Thin Films.
Nanostructured WO3 represents a promising material for electrochromic and sensing devices. In this scenario, electrodeposition is a promising low-cost approach for careful production. The electrodeposition of tungsten oxide film from a peroxo-tungstic-acid (PTA) solution is investigated. WO3 is synthetized onto Indium doped Tin Oxide (ITO) substrates, in a variety of shapes, from a fragmentary, thin layer up to a thick continuous film. Samples were investigated by scanning electron (SEM) and atomic force microscopy (AFM), Rutherford backscattering spectrometry (RBS), X-ray Diffraction analysis (XRD), energy gap measurement. Electrodeposition current curves are compared with characterization results to model the growth process. Early stages of electrodeposition are characterized by a transient cathodic current revealing an instantaneous nucleation followed by a diffusion limited process. A quantitative analysis of W deposition rate and current at working electrode validates a microscopic model for WO3 electrodeposition driving the process towards nanostructured versus continuous WO3 film.


Visible-Light-Driven "On"/"Off" Photochromism of a Polyoxometalate Diarylethene Coordination Complex.
Herein we report the first photochromic polyoxometalate (POM)-based diarylethene (DAE) coordination complex, prepared by ligation of two cobalt(III)-incorporated borotungstates [BIIIWVI11O39CoIII]6- with the ditopic pyridyl-containing diarylethene (C25H16N2F6S2). The solution-state composition, structure, and stability of the assembly were probed using 1H and 19F nuclear magnetic resonance spectroscopy (NMR), electrospray ionization quadrupolar time-of-flight mass spectrometry (ESI-QTOF-MS), ultraviolet-visible spectroscopy (UV-vis), and small-angle X-ray scattering (SAXS), revealing that the complex self-organizes to adopt a molecular dumbbell structure due to electrostatic and steric considerations. This conformation is a prerequisite for the photocyclization reaction. The assembly was found to be switchable between two states using visible light due to the perturbation of the DAE electronic structure on coordination to the POM. We present photophysical data, including the reaction quantum efficiency of the molecular switch in both directions measured using a custom-built quantum yield determination setup in addition to fatigue resistance on prolonged irradiation.


Physical and biotic determinants of space utilization by the Galapagos land iguana (Conolophus pallidus).
Home ranges of the Galapagos land iguana (Conolophus pallidus) were examined with respect to food availability and the thermal environment. Activity patterns, the amount of space used per day, and time required to use the entire home range were also investigated. The effects of, and the relationships between, these factors vary seasonally, as do home range sizes and preferred body temperatures.Food supplementation experiments resulted in only temporary reductions in use of space. Home range sizes were not different between the seasons with the least (Fall) and the most (Hot) food availalble, but home ranges were significantly smaller in Garua when food supplies were low, but not as low as in Fall. Calculations of metabolic expenditures in each season suggests that food availability alone does not explain seasonal patterns of home range size in this species.The thermal environment within each home range was characterized by microclimatic measurements and measurements of the area of sun, shade, and semi-shade. An index with units of m2h was used to quantify the thermal quality of each home range. Iguanas exploited optimal (with respect to body temperature) conditions more than would be expected from random use of their home ranges. Thermal transients (due to large body size) and optimal conditions were exploited to the largest degree in Fall.During Garua, low metabolic rates and time constraints imposed by an abundance of stressful thermal environments may result in small home ranges. In Fall, increased temperatures cause higher metabolic rates and allow more time for exploitation of the cooler portions of the home range, hence, home range sizes increase. In the Hot season, there is abundant food and optimal thermal conditions, but home ranges remain large. Searching for preferred foods may cause the large home ranges in this season.


Human platelet fraction arginine-vasopressin. Potential physiological role.
Arginine-vasopressin (AVP) immunoreactivity (Ir) has been found to be elevated in platelet-rich plasma. PlatAVP was defined as platelet-rich plasma Ir minus platelet-poor plasma Ir (Pavp). PlatAVP, Pavp, and synthetic AVP were found to have identical retention time on high performance liquid chromatography analysis and similar mobility on thin-layer chromatography. During a standard osmotic suppression-stimulation test, Pavp increased with plasma osmolality (Posm, mosmol/kg H2O); Pavp (pg/ml) = 0.98 (Posm -274.4), r = 0.57, P less than 0.001, n = 65; but PlatAVP was not significantly correlated with Posm and remained at 5 pg/ml. This PlatAVP concentration was estimated to represent a true intraplatelet AVP concentration of 0.4 to 3.7 X 10(-9) M. Binding studies on intact human platelets demonstrated specific binding sites for [3H]AVP (n = 16; BMax = 98 +/- 30 binding sites/platelet; Kd = 0.72 +/- 0.24 nM). This in vitro affinity association constant (Kd) was close to the estimated in vivo intraplatelet AVP concentration. Measurement of PlatAVP could estimate vasopressin bound to a specific platelet receptor.


Location of rectal cancer as determined using rectal magnetic resonance imaging, and its relationship with pulmonary metastasis.
The aim of this study was to evaluate the accuracy of 3-T magnetic resonance imaging (MRI) in locating rectal cancer, and to determine whether tumor location correlates with the incidence of pulmonary metastasis. A total of 146 patients with confirmed rectal adenocarcinoma underwent 3-T rectal MRI, and abdominal and chest computed tomography (CT) within 2 weeks of the endoscopic examination. We reviewed the distance between the mass and the anal verge recorded in the endoscopic reports of these patients. Two radiologists evaluated the same distance on MRI scans by using picture archiving and communications systems. Multiple factors including the tumor location, primary tumor and lymph node stage, lung and liver metastasis, pathologic differentiation, and the carcinoembryonic antigen level were evaluated. The correlation between tumor location on MRI and endoscopy was assessed, and significant factors influencing pulmonary metastasis were identified using multivariate logistic regression analysis. There was a statistically significant correlation between the tumor location established using MRI and the actual location recorded during endoscopy. The incidence of pulmonary metastasis was significantly higher in patients with lower rectal cancer (11/17, 65%) compared to those with upper rectal cancer (6/17, 35%; p<0.05). Factors associated with pulmonary metastasis were tumor location and the presence of liver metastasis. The accurate tumor location could be indicated using 3-T rectal MRI. Pulmonary metastasis occurred more frequently in patients with lower rectal cancer than in those with upper rectal cancer.


Evaluation of Quantified Social Perception Circuit Activity as a Neurobiological Marker of Autism Spectrum Disorder.
Autism spectrum disorder (ASD) is marked by social disability and is associated with dysfunction in brain circuits supporting social cue perception. The degree to which neural functioning reflects individual-level behavioral phenotype is unclear, slowing the search for functional neuroimaging biomarkers of ASD. To examine whether quantified neural function in social perception circuits may serve as an individual-level marker of ASD in children and adolescents. The cohort study was conducted at the Yale Child Study Center and involved children and adolescents diagnosed as having ASD and typically developing participants. Participants included a discovery cohort and a larger replication cohort. Individual-level social perception circuit functioning was assessed as functional magnetic resonance imaging brain responses to point-light displays of coherent vs scrambled human motion. Outcome measures included performance of quantified brain responses in affected male and female participants in terms of area under the receiver operating characteristic curve (AUC), sensitivity and specificity, and correlations between brain responses and social behavior. Of the 39 participants in the discovery cohort aged 4 to 17 years, 22 had ASD and 30 were boys. Of the 75 participants in the replication cohort aged 7 to 20 years, 37 had ASD and 52 were boys. A relative reduction in social perception circuit responses was identified in discovery cohort boys with ASD at an AUC of 0.75 (95% CI, 0.52-0.89; P = .01); however, typically developing girls and girls with ASD could not be distinguished (P = .54). The results were confirmed in the replication cohort, where brain responses were identified in boys with ASD at an AUC of 0.79 (95% CI, 0.64-0.91; P < .001) and failed to distinguish affected and unaffected girls (P = .82). Across both cohorts, boys were identified at an AUC of 0.77 (95% CI, 0.64-0.86) with corresponding sensitivity and specificity of 76% each. Additionally, brain responses were associated with social behavior in boys but not in girls. Quantified social perception circuit activity is a promising individual-level candidate neural marker of the male ASD behavioral phenotype. Our findings highlight the need to better understand effects of sex on social perception processing in relation to ASD phenotype manifestations.


TOP: Prospective Evaluation of a Volume Based, Computer Assisted Method for Transperineal Optimized Prostate Biopsy.
This study is a prospective evaluation of a volume-based, computer-assisted method for transperineal optimized prostate (TOP) biopsy. The TOP algorithm automates core planning for systematic prostate biopsies using the 3-dimensional organ contour and an alterable volume for tumors to be excluded. MRI-transrectal ultrasound fusion biopsy with MRI-targeted biopsies (TBs) and systematic-TOP biopsies were performed on 172 men between October 2013 and March 2014. Systematic biopsies were placed according to TOP for detection of tumor volumes >0.5 mL with a minimum of 80% organ coverage in prostates up to 50 mL (70% in larger organs). Median 24 TOP cores and 3 MRI-TBs have been placed. Prostate cancer (PCa) was detected in 112 of 172 (65%) of men; TOP detected 109 (97%) and TB 62 (55%). Significant cancer (Gleason score ≥7) was detected in 75 (44%) of men and of these TOP detected 73 of 75 (97%) and TB 51 of 75 (68%). Overall, systematic-TOP sampling significantly outperformed TB for the detection of both, all PCa as well as significant PCa (p < 0.0001, p = 0.0005). The TOP method is innovative by integrating the individual prostate volume and PCa volume detection thresholds. In the present cohort, it diagnosed more significant tumors than TB alone. However, at the same time, more low-risk tumors are detected.


Decreased brain volume in adults with childhood lead exposure.
Although environmental lead exposure is associated with significant deficits in cognition, executive functions, social behaviors, and motor abilities, the neuroanatomical basis for these impairments remains poorly understood. In this study, we examined the relationship between childhood lead exposure and adult brain volume using magnetic resonance imaging (MRI). We also explored how volume changes correlate with historic neuropsychological assessments. Volumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead concentrations. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. The most affected regions included frontal gray matter, specifically the anterior cingulate cortex (ACC). Areas of lead-associated gray matter volume loss were much larger and more significant in men than women. We found that fine motor factor scores positively correlated with gray matter volume in the cerebellar hemispheres; adding blood lead concentrations as a variable to the model attenuated this correlation. Childhood lead exposure is associated with region-specific reductions in adult gray matter volume. Affected regions include the portions of the prefrontal cortex and ACC responsible for executive functions, mood regulation, and decision-making. These neuroanatomical findings were more pronounced for males, suggesting that lead-related atrophic changes have a disparate impact across sexes. This analysis suggests that adverse cognitive and behavioral outcomes may be related to lead's effect on brain development producing persistent alterations in structure. Using a simple model, we found that blood lead concentration mediates brain volume and fine motor function.


Iron status and C-reactive protein in canine leishmaniasis.
To investigate the iron status, its relationship with C-reactive protein and the prognostic value of both in canine leishmaniasis. Eighty-six dogs with leishmaniasis and two control groups (healthy dogs and dogs with diseases other than leishmaniasis) were selected. Iron status indicators and C-reactive protein were compared between the three groups. Correlations between C-reactive protein and iron, ferritin and total iron-binding capacity were evaluated in dogs with leishmaniasis. Iron, total iron-binding capacity and ferritin were compared between dogs stratified according to similar C-reactive protein concentrations. The mortality rate at 30 days post-diagnosis was compared between groups. Iron status indicators and C-reactive protein were compared between survivors and non-survivors. Dogs with leishmaniasis had lower iron and total iron-binding capacity and higher ferritin and C-reactive protein. There was a significant but low correlation of C-reactive protein with iron, ferritin and total iron-binding capacity. Dogs with leishmaniasis had decreased iron and total iron-binding capacity and increased ferritin compared to other ill patients with similar C-reactive protein concentrations. Mortality was not significantly different between groups but non-survivor dogs with leishmaniasis had higher C-reactive protein and lower total iron-binding capacity. Inflammation contributes to the iron status alterations found in canine leishmaniasis but other mechanisms are likely involved. Low total iron-binding capacity and increased C-reactive protein are risk factors for outcome in canine leishmaniasis.


Humoral markers of active Epstein-Barr virus infection associate with anti-extractable nuclear antigen autoantibodies and plasma galectin-3 binding protein in systemic lupus erythematosus.
We investigated if signs of active Epstein-Barr virus and cytomegalovirus infections associate with certain autoantibodies and a marker of type I interferon activity in patients with systemic lupus erythematosus. IgM and IgG plasma levels against Epstein-Barr virus early antigen diffuse and cytomegalovirus pp52 were applied as humoral markers of ongoing/recently active Epstein-Barr virus and cytomegalovirus infections, respectively. Plasma galectin-3 binding protein served as a surrogate marker of type I interferon activity. The measurements were conducted in 57 systemic lupus erythematosus patients and 29 healthy controls using ELISAs. Regression analyses and univariate comparisons were performed for associative evaluation between virus serology, plasma galectin-3 binding protein and autoantibodies, along with other clinical and demographic parameters. Plasma galectin-3 binding protein concentrations were significantly higher in systemic lupus erythematosus patients (P = 0.009) and associated positively with Epstein-Barr virus early antigen diffuse-directed antibodies and the presence of autoantibodies against extractable nuclear antigens in adjusted linear regressions (B = 2.02 and 2.02, P = 0.02 and P = 0.002, respectively). Furthermore, systemic lupus erythematosus patients with anti-extractable nuclear antigens had significantly higher antibody levels against Epstein-Barr virus early antigen diffuse (P = 0.02). Our study supports a link between active Epstein-Barr virus infections, positivity for anti-extractable nuclear antigens and increased plasma galectin-3 binding protein concentrations/type I interferon activity in systemic lupus erythematosus patients.


Cladophora (Chlorophyta) spp. harbor human bacterial pathogens in nearshore water of Lake Michigan.
Cladophora glomerata, a macrophytic green alga, is commonly found in the Great Lakes, and significant accumulations occur along shorelines during the summer months. Recently, Cladophora has been shown to harbor high densities of the fecal indicator bacteria Escherichia coli and enterococci. Cladophora may also harbor human pathogens; however, until now, no studies to address this question have been performed. In the present study, we determined whether attached Cladophora, obtained from the Lake Michigan and Burns Ditch (Little Calumet River, Indiana) sides of a breakwater during the summers of 2004 and 2005, harbored the bacterial pathogens Shiga toxin-producing Escherichia coli (STEC), Salmonella, Shigella, and Campylobacter. The presence of potential pathogens and numbers of organisms were determined by using cultural methods and by using conventional PCR, most-probable-number PCR (MPN-PCR), and quantitative PCR (QPCR) performed with genus- and toxin-specific primers and probes. While Shigella and STEC were detected in 100% and 25%, respectively, of the algal samples obtained near Burns Ditch in 2004, the same pathogens were not detected in samples collected in 2005. MPN-PCR and QPCR allowed enumeration of Salmonella in 40 to 80% of the ditch- and lakeside samples, respectively, and the densities were up to 1.6 x 10(3) cells per g Cladophora. Similarly, these PCR methods allowed enumeration of up to 5.4 x 10(2) Campylobacter cells/g Cladophora in 60 to 100% of lake- and ditchside samples. The Campylobacter densities were significantly higher (P < 0.05) in the lakeside Cladophora samples than in the ditchside Cladophora samples. DNA fingerprint analyses indicated that genotypically identical Salmonella isolates were associated with geographically and temporally distinct Cladophora samples. However, Campylobacter isolates were genetically diverse. Since animal hosts are thought to be the primary habitat for Campylobacter and Salmonella species, our results suggest that Cladophora is a likely secondary habitat for pathogenic bacteria in Lake Michigan and that the association of these bacteria with Cladophora warrants additional studies to assess the potential health impact on beach users.


Traumatic brain injury history and progression from mild cognitive impairment to Alzheimer disease.
To examine whether history of traumatic brain injury (TBI) is associated with more rapid progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Data from 2,719 subjects with MCI were obtained from the National Alzheimer's Coordinating Center. TBI was categorized based on presence (TBI+) or absence (TBI-) of reported TBI with loss of consciousness (LOC) without chronic deficit occurring >1 year prior to diagnosis of MCI. Survival analyses were used to determine if a history of TBI predicted progression from MCI to AD up to 8 years. Random regression models were used to examine whether TBI history also predicted rate of decline on the Clinical Dementia Rating scale Sum of Boxes score (CDR-SB) among subjects who progress to AD. Across 8 years, TBI history was not significantly associated with progression from MCI to a diagnosis of AD in unadjusted (HR = 0.80; 95% CI [0.63, 1.01]; p = .06) and adjusted (p = .15) models. Similarly, a history of TBI was a nonsignificant predictor for rate of decline on CDR-SB among subjects who progressed to AD (b = 0.15, p = .38). MCI was, however, diagnosed a mean of 2.6 years earlier (p < .001) in TBI+ subjects compared with the TBI- group. A history of TBI with LOC was not associated with progression from MCI to AD, but was linked to an earlier age of MCI diagnosis. These findings add to a growing literature suggesting that TBI might reduce the threshold for onset of MCI and certain neurodegenerative conditions, but appears unrelated to progression from MCI to AD. (PsycINFO Database Record


Long-term remission with rituximab in refractory leucine-rich glioma inactivated 1 antibody encephalitis.
Autoimmune encephalitis associated with antibodies to leucine-rich glioma inactivated 1 (LGI1) is recently described and there is a lack of detailed reports on the treatment of relapsing or refractory cases and long-term outcomes. Two case reports are presented. Both cases had faciobrachial dystonic seizures (FBDS) and received rituximab after relapsing or refractory disease. Both cases achieved sustained clinical remission of up to 15 and 56 months respectively. Rituximab use allowed withdrawal of corticosteroids and was well tolerated. Randomized clinical trials are needed in LGI1 encephalitis and other autoimmune encephalitides.


Changes in fractal dimension during aggregation.
Experiments were performed to evaluate temporal changes in the fractal dimension of aggregates formed during flocculation of an initially monodisperse suspension of latex microspheres. Particle size distributions and aggregate geometrical information at different mixing times were obtained using a non-intrusive optical sampling and digital image analysis technique, under variable conditions of mixing speed, coagulant (alum) dose and particle concentration. Pixel resolution required to determine aggregate size and geometric measures including the fractal dimension is discussed and a quantitative measure of accuracy is developed. The two-dimensional fractal dimension was found to range from 1.94 to 1.48, corresponding to aggregates that are either relatively compact or loosely structured, respectively. Changes in fractal dimension are explained using a conceptual model, which describes changes in fractal dimension associated with aggregate growth and changes in aggregate structure. For aggregation of an initially monodisperse suspension, the fractal dimension was found to decrease over time in the initial stages of floc formation.


Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment.
The synovial tissue is a primary target of many inflammatory arthropathies, including psoriatic arthritis (PsA). Identification of proinflammatory molecules in the synovium may help to identify potentially therapeutic targets. To investigate extensively the features of cell infiltration and expression of mediators of inflammation and joint destruction in the synovium of patients with PsA compared with patients with rheumatoid arthritis matched for disease duration and use of drugs. Multiple synovial tissue biopsy specimens were obtained by arthroscopy from an inflamed joint in 19 patients with PsA (eight oligoarthritis, 11 polyarthritis) and 24 patients with rheumatoid arthritis. Biopsy specimens were analysed by immunohistochemistry to detect T cells, plasma cells, fibroblast-like synoviocytes, macrophages, proinflammatory cytokines, matrix metalloproteinases and tissue inhibitor metalloproteinase-1, adhesion molecules and vascular markers. Stained sections were evaluated by digital image analysis. The synovial infiltrate of patients with PsA and rheumatoid arthritis was comparable with regard to numbers of fibroblast-like synoviocytes and macrophages. T cell numbers were considerably lower in the synovium of patients with PsA. The number of plasma cells also tended to be lower in PsA. The expression of tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, IL6 and IL18 was as high in PsA as in rheumatoid arthritis. The expression of matrix metalloproteinases, adhesion molecules and vascular markers was comparable for PsA and rheumatoid arthritis. These data show increased proinflammatory cytokine expression in PsA synovium, comparable to results obtained for rheumatoid arthritis, and support the notion that, in addition to TNFalpha blockade, there may be a rationale for treatments directed at IL1beta, IL6 and IL18.


Catechol-based biomimetic functional materials.
Catechols are found in nature taking part in a remarkably broad scope of biochemical processes and functions. Though not exclusively, such versatility may be traced back to several properties uniquely found together in the o-dihydroxyaryl chemical function; namely, its ability to establish reversible equilibria at moderate redox potentials and pHs and to irreversibly cross-link through complex oxidation mechanisms; its excellent chelating properties, greatly exemplified by, but by no means exclusive, to the binding of Fe(3+); and the diverse modes of interaction of the vicinal hydroxyl groups with all kinds of surfaces of remarkably different chemical and physical nature. Thanks to this diversity, catechols can be found either as simple molecular systems, forming part of supramolacular structures, coordinated to different metal ions or as macromolecules mostly arising from polymerization mechanisms through covalent bonds. Such versatility has allowed catechols to participate in several natural processes and functions that range from the adhesive properties of marine organisms to the storage of some transition metal ions. As a result of such an astonishing range of functionalities, catechol-based systems have in recent years been subject to intense research, aimed at mimicking these natural systems in order to develop new functional materials and coatings. A comprehensive review of these studies is discussed in this paper.


Gating interaction maps reveal a noncanonical electromechanical coupling mode in the Shaker K+ channel.
Membrane potential regulates the activity of voltage-dependent ion channels via specialized voltage-sensing modules, but the mechanisms involved in coupling voltage-sensor movement to pore opening remain unclear owing to a lack of resting state structures and robust methods to identify allosteric pathways. Here, using a newly developed interaction-energy analysis, we probe the interfaces of the voltage-sensing and pore modules in the Drosophila Shaker K+ channel. Our measurements reveal unexpectedly strong equilibrium gating interactions between contacts at the S4 and S5 helices in addition to those between S6 and the S4-S5 linker. Network analysis of MD trajectories shows that the voltage-sensor and pore motions are linked by two distinct pathways: a canonical pathway through the S4-S5 linker and a hitherto unknown pathway akin to rack-and-pinion coupling involving the S4 and S5 helices. Our findings highlight the central role of the S5 helix in electromechanical transduction in the voltage-gated ion channel (VGIC) superfamily.


Metabolic Reprogramming in Cancer Is Induced to Increase Proton Production.
Considerable metabolic reprogramming has been observed in a conserved manner across multiple cancer types, but their true causes remain elusive. We present an analysis of around 50 such reprogrammed metabolisms (RM) including the Warburg effect, nucleotide de novo synthesis, and sialic acid biosynthesis in cancer. Analyses of the biochemical reactions conducted by these RMs, coupled with gene expression data of their catalyzing enzymes, in 7,011 tissues of 14 cancer types, revealed that all RMs produce more H+ than their original metabolisms. These data strongly support a model that these RMs are induced or selected to neutralize a persistent intracellular alkaline stress due to chronic inflammation and local iron overload. To sustain these RMs for survival, cells must find metabolic exits for the nonproton products of these RMs in a continuous manner, some of which pose major challenges, such as nucleotides and sialic acids, because they are electrically charged. This analysis strongly suggests that continuous cell division and other cancerous behaviors are ways for the affected cells to remove such products in a timely and sustained manner. As supporting evidence, this model can offer simple and natural explanations to a range of long-standing open questions in cancer research including the cause of the Warburg effect. SIGNIFICANCE: Inhibiting acidifying metabolic reprogramming could be a novel strategy for treating cancer.


Mechismo: predicting the mechanistic impact of mutations and modifications on molecular interactions.
Systematic interrogation of mutation or protein modification data is important to identify sites with functional consequences and to deduce global consequences from large data sets. Mechismo (mechismo.russellab.org) enables simultaneous consideration of thousands of 3D structures and biomolecular interactions to predict rapidly mechanistic consequences for mutations and modifications. As useful functional information often only comes from homologous proteins, we benchmarked the accuracy of predictions as a function of protein/structure sequence similarity, which permits the use of relatively weak sequence similarities with an appropriate confidence measure. For protein-protein, protein-nucleic acid and a subset of protein-chemical interactions, we also developed and benchmarked a measure of whether modifications are likely to enhance or diminish the interactions, which can assist the detection of modifications with specific effects. Analysis of high-throughput sequencing data shows that the approach can identify interesting differences between cancers, and application to proteomics data finds potential mechanistic insights for how post-translational modifications can alter biomolecular interactions.


Learning about learning: Mining human brain sub-network biomarkers from fMRI data.
Modeling the brain as a functional network can reveal the relationship between distributed neurophysiological processes and functional interactions between brain structures. Existing literature on functional brain networks focuses mainly on a battery of network properties in "resting state" employing, for example, modularity, clustering, or path length among regions. In contrast, we seek to uncover functionally connected subnetworks that predict or correlate with cohort differences and are conserved within the subjects within a cohort. We focus on differences in both the rate of learning as well as overall performance in a sensorimotor task across subjects and develop a principled approach for the discovery of discriminative subgraphs of functional connectivity based on imaging acquired during practice. We discover two statistically significant subgraph regions: one involving multiple regions in the visual cortex and another involving the parietal operculum and planum temporale. High functional coherence in the former characterizes sessions in which subjects take longer to perform the task, while high coherence in the latter is associated with high learning rate (performance improvement across trials). Our proposed methodology is general, in that it can be applied to other cognitive tasks, to study learning or to differentiate between healthy patients and patients with neurological disorders, by revealing the salient interactions among brain regions associated with the observed global state. The discovery of such significant discriminative subgraphs promises a better data-driven understanding of the dynamic brain processes associated with high-level cognitive functions.


How depression and other mental health problems can affect future living standards of those out of the labour force.
To estimate the extent to which those who exit the workforce early due to mental health problems have less savings by the time they reach retirement age. Using Health & WealthMOD--a microsimulation model of Australians aged 45-64 years that predicts accumulated savings at age 65, regression models were used to analyse the differences between the projected savings and the retirement incomes of people at age 65 for those currently working with no chronic condition, and people not in the labour force due to mental health problems. Females who retire early due to depression have a median value of total savings by the time they are 65 of $300. For those with other mental health problems the median figure was $0. This is far lower than the median value of $227,900 for females with no chronic condition who remained employed full-time. Males showed similar differences. Both males and females who were out of the labour force due to depression or other mental health problems had at least 97% (95% CI: -99.9% to -68.7%) less savings and retirement income by age 65 that those who remained employed full-time. People who retire from the labour force early due to mental health problems will face long term financial disadvantage compared to people who are able to remain in employment.


Change of the aortic elasticity in rheumatoid arthritis: Relationship to associated cardiovascular risk factors.
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disease, which is associated with an excess of cardiovascular events. A decrease in the compliance of the arterial system, termed arterial stiffness, results in increased cardiac workload. Primary prevention of cardiovascular disease (CVD) is a priority for modern medicine. Therefore, further studies are required to explore the mechanisms through which CVD increases in RA. This case-control study was performed to detect possible change of aortic elasticity in patients with RA, and to estimate the impact of different cardiovascular and atherogenic risk factors on the severity of arterial stiffness. Sixty-three consecutive adults with RA were enrolled for the study (case group). Forty-one healthy adults matched for age and gender were considered as a control group. All were subjected to assessment of aortic stiffness index and various cardiovascular risk factors. Patients with rheumatoid disease (case group) were divided by their aortic stiffness index status to two groups (A and B, with and without aortic stiffness, respectively). Aortic stiffness was present in 31.7% of the RA patients. Age of the patients, duration of RA, smoking index, waist circumference, triglycerides levels, and CRP were significantly higher in patients with aortic stiffness. RA is associated with decreased elasticity of the aorta in both genders, and such changes seem to be higher in the presence of visceral obesity, smoking, high triglycerides, and extraarticular disease severity.


First Report of Leaf Spot Caused by Colletotrichum spaethianum on Peucedanum praeruptorum in China.
Peucedanum praeruptorum Dunn, a traditional Chinese medicinal herb, is an important crop in Ningguo, China. Since 2010, leaf spot symptoms were observed yearly starting in June. Blighted leaf areas on individual plants ranged from 10 to 25% in many fields, and up to 200 ha were affected each year. Symptoms consisted of small, brown, necrotic spots uniformly distributed on the 1- to 2-week-old leaves. Small tissue pieces from the edges of lesions were disinfected in 2% NaClO for 3 min, rinsed twice in distilled water, plated on potato dextrose agar (PDA), and incubated at 25°C in darkness for 4 days. Single spore isolations were obtained for six strains. When inoculated on SNA media, the six strains produced typical septate mycelium, with the young hyphae hyaline and aged ones white greyish. Setae of the strains on SNA were brown, tip acute, 2- to 3-septate, and 32.5 to 85.6 μm long. Conidiogenous cells were hyaline, cylindrical, 2- to 3-septate, 6.2 to 16.5 μm in length, and 2.8 to 4.3 μm in width. The mature conidia were slightly curved, with round apex and truncate base, 1 to 5 oil globules, and were 13.3 to 23.8 μm in length and 3.0 to 3.9 μm in width, respectively. Appressoria were solitary or in loose groups, dark brown, irregular shapes, and were 6.8 to 9.2 μm in length and 4.3 to 7.1 μm in width. PCR amplification was carried out by utilizing the universal rDNA-ITS primer pair ITS4/ITS5 (1) and the actin gene primer pair ACT-512F and ACT-783R (2). The PCR products of ITS (GenBank Accession No. KC913201) and actin gene (KC913202) from six isolates were identical, respectively, and shared 100% identity to the ITS sequence of strain CBS 167.49 of Colletotrichum spaethianum (GU227807.1) and 99% similarity to the actin gene of strain CBS 167.49 of C. spaethianum (GU227905.1), which was isolated from Hosta sieboldiana in Germany (3). Based on the above, the isolates were identified as C. spaethianum. To confirm pathogenicity, conidial suspensions (105 conidia ml-1) of each of the six isolates were sprayed on four leaves per plant on five 6-month-old P. praeruptorum plants. Control plants were sprayed with water. Plants were maintained at 28°C in a greenhouse with constant humidity (RH 90%) and a 12-h photoperiod of fluorescent light. Symptoms similar to the original ones started to appear after 10 days, while the control plants remained healthy. The tests were repeated three times and the fungus was recovered and identified as C. spaethianum by both morphology and molecular characterization. To our knowledge, this is the first report of C. spaethianum causing leaf spot on P. praeruptorum in China. Since the C. spaethianum infections pose a serious threat to P. praeruptorum production, this disease needs to be considered for developing effective control strategies. References: (1) I. Carbone and L. M. Kohn. Mycologia 91:553, 1999. (2) U. Damm et al. Fung. Divers. 39:45, 2009. (3) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, 1990.


Evaluating conditional release in not guilty by reason of insanity acquittees: a prospective follow-up study in Virginia.
Detailed research on treatment and risk management approaches with not guilty by reason of insanity acquittees (NGRI) during their conditional release is needed as states increasingly use community-based services for these individuals. Grounded in case law, and supported by follow-up studies demonstrating low recidivism rates, states have been encouraged in their efforts to conditionally release NGRI acquittees. The authors evaluated a state-wide sample of 127 NGRI acquittees released into the community after spending a mean of 61.63 months (SD = 76.54) in the hospital. One hundred individuals were committed to the hospital for lengthier treatment (M hospital time = 77.23 months, SD = 79.84), but 27 individuals were released to the community after a relatively short hospital stay (M hospital time = 5.60 months, SD = 3.01). Regarding release, 96 individuals (75.6%) maintained their conditional release. After evaluating a host of demographic and standardized risk data, the following variables predicted revocation on conditional release: previous failure on conditional release, nonadherence with hospital treatment, dangerousness to others, and previous violent charges. A multivariate survival analysis determined criminal behavior and previous failure on conditional release predicted time to revocation. The results of this study demonstrate the importance of considering standardized risk variables in the community-based management of forensic patients. In addition, the data are supportive of continued attempts at moving insanity acquittees from the hospital to the community via conditional release.


Multiple Sparse Representations Classification.
Sparse representations classification (SRC) is a powerful technique for pixelwise classification of images and it is increasingly being used for a wide variety of image analysis tasks. The method uses sparse representation and learned redundant dictionaries to classify image pixels. In this empirical study we propose to further leverage the redundancy of the learned dictionaries to achieve a more accurate classifier. In conventional SRC, each image pixel is associated with a small patch surrounding it. Using these patches, a dictionary is trained for each class in a supervised fashion. Commonly, redundant/overcomplete dictionaries are trained and image patches are sparsely represented by a linear combination of only a few of the dictionary elements. Given a set of trained dictionaries, a new patch is sparse coded using each of them, and subsequently assigned to the class whose dictionary yields the minimum residual energy. We propose a generalization of this scheme. The method, which we call multiple sparse representations classification (mSRC), is based on the observation that an overcomplete, class specific dictionary is capable of generating multiple accurate and independent estimates of a patch belonging to the class. So instead of finding a single sparse representation of a patch for each dictionary, we find multiple, and the corresponding residual energies provides an enhanced statistic which is used to improve classification. We demonstrate the efficacy of mSRC for three example applications: pixelwise classification of texture images, lumen segmentation in carotid artery magnetic resonance imaging (MRI), and bifurcation point detection in carotid artery MRI. We compare our method with conventional SRC, K-nearest neighbor, and support vector machine classifiers. The results show that mSRC outperforms SRC and the other reference methods. In addition, we present an extensive evaluation of the effect of the main mSRC parameters: patch size, dictionary size, and sparsity level.


Sequence variations at I260 and A1731 contribute to persistent currents in Drosophila sodium channels.
Tetrodotoxin-sensitive persistent sodium currents, INaP, that activate at subthreshold voltages, have been detected in numerous vertebrate and invertebrate neurons. These currents are believed to be critical for regulating neuronal excitability. However, the molecular mechanism underlying INaP is controversial. In this study, we identified an INaP with a broad range of voltage dependence, from -60mV to 20mV, in a Drosophila sodium channel variant expressed in Xenopus oocytes. Mutational analysis revealed that two variant-specific amino acid changes, I260T in the S4-S5 linker of domain I (ILS4-S5) and A1731V in the voltage sensor S4 of domain IV (IVS4), contribute to the INaP. I260T is critical for the portion of INaP at hyperpolarized potentials. The T260-mediated INaP is likely the result of window currents flowing in the voltage range where the activation and inactivation curves overlap. A1731V is responsible for impaired inactivation and contributes to the portion of INaP at depolarized potentials. Furthermore, A1731V causes enhanced activity of two site-3 toxins which induce persistent currents by inhibiting the outward movement of IVS4, suggesting that A1731V inhibits the outward movement of IVS4. These results provided molecular evidence for the involvement of distinct mechanisms in the generation of INaP: T260 contributes to INaP via enhancement of the window current, whereas V1731 impairs fast inactivation probably by inhibiting the outward movement of IVS4.


Dysregulation of TFEB contributes to manganese-induced autophagic failure and mitochondrial dysfunction in astrocytes.
Epidemiological and clinical studies have long shown that exposure to high levels of heavy metals are associated with increased risks of neurodegenerative diseases. It is widely accepted that autophagic dysfunction is involved in pathogenesis of various neurodegenerative disorders; however, the role of heavy metals in regulation of macroautophagy/autophagy is unclear. Here, we show that manganese (Mn) induces a decline in nuclear localization of TFEB (transcription factor EB), a master regulator of the autophagy-lysosome pathway, leading to autophagic dysfunction in astrocytes of mouse striatum. We further show that Mn exposure suppresses autophagic-lysosomal degradation of mitochondria and induces accumulation of unhealthy mitochondria. Activation of autophagy by rapamycin or TFEB overexpression ameliorates Mn-induced mitochondrial respiratory dysfunction and reactive oxygen species (ROS) generation in astrocytes, suggesting a causal relation between autophagic failure and mitochondrial dysfunction in Mn toxicity. Taken together, our data demonstrate that Mn inhibits TFEB activity, leading to impaired autophagy that is causally related to mitochondrial dysfunction in astrocytes. These findings reveal a previously unappreciated role for Mn in dysregulation of autophagy and identify TFEB as a potential therapeutic target to mitigate Mn toxicity. BECN1: beclin 1; CTSD: cathepsin D; DMEM: Dulbecco's Modified Eagle Medium; GFAP: glial fibrillary acid protein; GFP: green fluorescent protein; HBSS: hanks balanced salt solution; LAMP: lysosomal-associated membrane protein; LDH: lactate dehydrogenase; Lys Inh: lysosomal inhibitors; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; Mn: manganese; MTOR: mechanistic target of rapamycin kinase; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PI: propidium iodide; ROS: reactive oxygen species; s.c.: subcutaneous; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB.


A critical appraisal of bleeding events reported in venous thromboembolism prevention trials of patients undergoing hip and knee arthroplasty.
Anticoagulants are effective for the prevention of venous thromboembolism (VTE) but cause bleeding. Interpretation of the risks and benefits of new anticoagulant regimens for VTE prevention is complicated by a lack of standardized definitions and reporting of bleeding. We reviewed the reporting of bleeding in randomized controlled trials of new anticoagulants compared with standard doses of enoxaparin in hip and knee arthroplasty, and examined the possible impact of differences in the definition of major bleeding on interpretation of the trial results. Electronic searches identified 16 phase III trials published between 2001 and 2010 involving 41,265 patients comparing one of five new anticoagulants with a common comparator, enoxaparin. Major bleeding rates in patients treated with enoxaparin ranged from 0.1% to 3.1% in hip arthroplasty trials and from 0.2% to 1.4% in knee arthroplasty trials. In studies that excluded surgical-site bleeding from the definition, major bleeding rates were about 10-fold lower than in those which included surgical-site bleeding. Within the individual trials, the choice of bleeding definition and the methods of assessment of bleeding influenced the conclusions regarding the risk of bleeding with new anticoagulant regimens relative to enoxaparin. Eight of the 16 studies demonstrated a ≥ 40% relative risk differences in major bleeding between treatment groups but the difference was statistically significant in only two of these trials. Randomized VTE prevention trials report markedly different rates of major bleeding despite similar patient populations and doses and durations of anticoagulant prophylaxis and were underpowered to detect modest differences in patient-important bleeding events. Standardization of bleeding definitions and reporting seems desirable.


A Comprehensive Drosophila melanogaster Transcription Factor Interactome.
Combinatorial interactions among transcription factors (TFs) play essential roles in generating gene expression specificity and diversity in metazoans. Using yeast 2-hybrid (Y2H) assays on nearly all sequence-specific Drosophila TFs, we identified 1,983 protein-protein interactions (PPIs), more than doubling the number of currently known PPIs among Drosophila TFs. For quality assessment, we validated a subset of our interactions using MITOMI and bimolecular fluorescence complementation assays. We combined our interactome with prior PPI data to generate an integrated Drosophila TF-TF binary interaction network. Our analysis of ChIP-seq data, integrating PPI and gene expression information, uncovered different modes by which interacting TFs are recruited to DNA. We further demonstrate the utility of our Drosophila interactome in shedding light on human TF-TF interactions. This study reveals how TFs interact to bind regulatory elements in vivo and serves as a resource of Drosophila TF-TF binary PPIs for understanding tissue-specific gene regulation.


Broad expression analysis of human ANTXR1/TEM8 transcripts reveals differential expression and novel splizce variants.
Tumor endothelial marker 8 (TEM8; ANTXR1) is one of two anthrax toxin receptors; the other is capillary morphogenesis gene 2 protein (CMG2; ANTXR2). TEM8 shows enhanced expression in certain tumor endothelia, and is thought to be a player in tumor vasculature formation. However, a comprehensive expression profile of individual TEM8 variants in normal or cancerous tissues is lacking. In this work we carried out an extensive analysis of all splice variants of human TEM8 in 12 digestive tissues, and 8 each fetal and adult tissues, 6 of them cognate pairs. Using variant-specific primers, we first ascertained the status of full-length transcripts by nested PCR. We then carried out quantitative analysis of each transcript by real-time PCR. Three splice variants of TEM8 were reported before, two single-pass integral membrane forms (V1 and V2) and one secreted (V3). Our analysis has revealed two new variants, one encoding a membrane-bound form of the receptor and the other secreted, which we have designated V4 and V5, respectively. All tissues had V1, V2, V3, and V4, but only prostate had V5. Real-time PCR revealed that all variants are present at different levels in various tissues. V3 appeared the most abundant of all. To ascertain its functionality for anthrax toxin, we expressed the newly identified form V4 in a receptor-negative host cell, and included V1 and V2 for comparison. Cytotoxicity, toxin binding, and internalization assays showed V4 to be as efficient a receptor as V1 and V2.


Experimental heat treatment of silcrete implies analogical reasoning in the Middle Stone Age.
Siliceous rocks that were not heated to high temperatures during their geological formation display improved knapping qualities when they are subjected to controlled heating. Experimental heat treatment of South African silcrete, using open fires of the kind used during the Middle Stone Age, shows that the process needed careful management, notwithstanding recent arguments to the contrary. Silcrete blocks fractured when heated on the surface of open fires or on coal beds, but were heated without mishap when buried in sand below a fire. Three silcrete samples, a control, a block heated underground with maximum temperature between 400 and 500 °C and a block heated in an open fire with maximum temperature between 700 and 800 °C, were analysed with X-ray powder diffraction (XRD), X-ray fluorescence (XRF), optical microscopy, and both Fourier transform infrared (FTIR) and Raman spectroscopy. The results show that the volume expansion during the thermally induced α- to β-quartz phase transformation and the volume contraction during cooling play a major role in the heat treatment of silcrete. Rapid heating or cooling through the phase transformation at 573 °C will cause fracture of the silcrete. Successful heat treatment requires controlling surface fire temperatures in order to obtain the appropriate underground temperatures to stay below the quartz inversion temperature. Heat treatment of rocks is a transformative technology that requires skilled use of fire. This process involves analogical reasoning, which is an attribute of complex cognition.


Accuracy of frozen section in the diagnosis of liver mass lesions.
To evaluate the diagnostic accuracy of intraoperative frozen sections diagnosis of liver lesions thought to be malignant tumours. 285 frozen sections of liver from 173 patients were reviewed. The examinations were done between 1998 and 2004. Final histological diagnosis was divided into positive (32%) and negative (68%) for malignancy. In four cases (2%), diagnosis was deferred to paraffin section. There was one false positive and two false negative diagnoses. Sensitivity was 96.9% and specificity was 99.1%, and the overall accuracy to determine the lesions was 95%. The cases were further analysed to ascertain the nature of diagnostic difficulties, which comprised pathological misinterpretation, sampling error, and technical imperfections. Biliary hamartoma was the most common entity that was confused with malignant tumours in frozen sections. The data are in accordance with those of similar studies in other sites, and confirm that the frozen section is an accurate and reliable method for intraoperative diagnosis of suspected liver lesions.


Identification and modeling of genes with diurnal oscillations from microarray time series data.
Behavior of living organisms is strongly modulated by the day and night cycle giving rise to a cyclic pattern of activities. Such a pattern helps the organisms to coordinate their activities and maintain a balance between what could be performed during the "day" and what could be relegated to the "night." This cyclic pattern, called the "Circadian Rhythm," is a biological phenomenon observed in a large number of organisms. In this paper, our goal is to analyze transcriptome data from Cyanothece for the purpose of discovering genes whose expressions are rhythmic. We cluster these genes into groups that are close in terms of their phases and show that genes from a specific metabolic functional category are tightly clustered, indicating perhaps a "preferred time of the day/night" when the organism performs this function. The proposed analysis is applied to two sets of microarray experiments performed under varying incident light patterns. Subsequently, we propose a model with a network of three phase oscillators together with a central master clock and use it to approximate a set of "circadian-controlled genes" that can be approximated closely.


Preclinical assessment of comfort and secure fit of thermobrachytherapy surface applicator (TBSA) on volunteer subjects.
A thermobrachytherapy surface applicator (TBSA) was developed for simultaneous heat and brachytherapy treatment of chest wall (CW) recurrence of breast cancer. The ability to comfortably secure the applicator over the upper torso relative to the CW target throughout treatment is assessed on volunteers. Male and postmastectomy female volunteers were enrolled to evaluate applicator secure fit to CW. Female subjects with intact breast were also enrolled to assess the ability to treat challenging cases. Magnetic resonance (MR) images of volunteers wearing a TBSA over the upper torso were acquired once every 15 minutes for 90 minutes. Applicator displacement over this time period required for treatment preplanning and delivery was assessed using MR visible markers. Applicator comfort and tolerability were assessed using a questionnaire. Probability estimates of applicator displacements were used to investigate dosimetric impact for the worst-case variation in radiation source-to-skin distance for 5 and 10 mm deep targets spread 17 × 13 cm on a torso phantom. Average and median displacements along lateral and radial directions were less than 1.2 mm over 90 minutes for all volunteers. Maximum lateral and radial displacements were measured to be less than 1 and 1.5 mm, respectively, for all CW volunteers and less than 2 mm for intact breast volunteers, excluding outliers. No complaint of pain or discomfort was reported. Phantom treatment planning for the maximum displacement of 2 mm indicated < 10% increase in skin dose with < 5% loss of homogeneity index (HI) for -2 mm uniform HDR source displacement. For +2 mm uniform displacement, skin dose decreased and HI increased by 20%. The volunteer study demonstrated that such large and uniform displacements should be rare for CW subjects, and the measured variation is expected to be low for multifraction conformal brachytherapy treatment.


Nijmegen breakage syndrome fibroblasts expressing the C-terminal truncated NBN(p70) protein undergo p38/MK2-dependent premature senescence.
Fibroblasts from the progeroid Nijmegen breakage syndrome that express a truncated version of the nibrin protein (NBN(p70)) undergo premature senescence and have an enlarged morphology with high levels of senescence-associated β-galactosidase, although they do not have F-actin stress fibres. Growth of these fibroblasts in the continuous presence of p38 inhibitors resulted in a large increase in replicative capacity and changed the cellular morphology so that the cells resembled young normal fibroblasts. A similar effect was seen using an inhibitor of the p38 downstream effector kinase MK2. These data suggest that NBN(p70) expressing cells undergo a degree of stress-induced replicative senescence via p38/MK2 activation, potentially due to increased telomere dysfunction, that may play a role in the progeroid features seen in this syndrome.


Effect of defects on the intrinsic strength and stiffness of graphene.
It is important from a fundamental standpoint and for practical applications to understand how the mechanical properties of graphene are influenced by defects. Here we report that the two-dimensional elastic modulus of graphene is maintained even at a high density of sp(3)-type defects. Moreover, the breaking strength of defective graphene is only ~14% smaller than its pristine counterpart in the sp(3)-defect regime. By contrast, we report a significant drop in the mechanical properties of graphene in the vacancy-defect regime. We also provide a mapping between the Raman spectra of defective graphene and its mechanical properties. This provides a simple, yet non-destructive methodology to identify graphene samples that are still mechanically functional. By establishing a relationship between the type and density of defects and the mechanical properties of graphene, this work provides important basic information for the rational design of composites and other systems utilizing the high modulus and strength of graphene.


Environmental, occupational, and personal factors related to the prevalence of sick building syndrome in the general population.
Possible relations between prevalence of sick building syndrome (SBS) and environmental, occupational, and personal factors were studied in a random sample (0.1%) of the general population aged 20-65 in a three county region in middle Sweden. Childhood exposure to environmental tobacco smoke from smoking mothers and a childhood in urban areas was related to SBS symptoms. Current urban residency, fresh paint, and preschool children in the dwelling were also related to symptoms. Other residential factors such as age of building, type of building, degree of crowding, mechanical ventilation, or signs of moisture or mould growth were not related to symptoms. Other factors related to symptoms were history of atopy, allergy to nickel, proneness to infection, hyperreactivity, static electricity, work with video display units (VDU), work satisfaction, and climate of cooperation at work. Age, sex, marital state, education level, work stress, obesity, current or earlier smoking, regular physical exercise, or occupational exposure to chemicals did not correlate with symptoms. Women had a higher proportion of symptoms than men but these differences were not significant when adjusting for differences in allergy to nickel, hyperreactivity, and proneness to infection. Maternal smoking was related to a twofold increase of both atopy and allergy to nickel in the adult offspring. Eye symptoms were most common in administrative, managerial, and service work. Airway symptoms were most common in transport and communication work. Dermal symptoms were most common in professional and technical and related work. General symptoms were most common in service, health, hospital, and social work. The lowest prevalence of symptoms was found in agricultural, forestry, and sales work. Women and subjects allergic to nickel worked more often in occupations without exposure to chemicals, but no evidence was found for selection mechanisms causing sensitive persons to move from exposed to unexposed occupations. It was concluded that symptoms included in SBS are common in the general population, and of multifactorial origin related to both personal, occupational, and residential factors, and certain environmental exposures such as maternal smoking, the urban environment, VDU work, and volatile organic hydrocarbons from newly painted dwellings.


Asthma phenotypes in inner-city children.
Children with asthma in low-income urban areas have high morbidity. Phenotypic analysis in these children is lacking, but may identify characteristics to inform successful tailored management approaches. We sought to identify distinct asthma phenotypes among inner-city children receiving guidelines-based management. Nine inner-city asthma consortium centers enrolled 717 children aged 6 to 17 years. Data were collected at baseline and prospectively every 2 months for 1 year. Participants' asthma and rhinitis were optimally managed by study physicians on the basis of guidelines. Cluster analysis using 50 baseline and 12 longitudinal variables was performed in 616 participants completing 4 or more follow-up visits. Five clusters (designated A through E) were distinguished by indicators of asthma and rhinitis severity, pulmonary physiology, allergy (sensitization and total serum IgE), and allergic inflammation. In comparison to other clusters, cluster A was distinguished by lower allergy/inflammation, minimally symptomatic asthma and rhinitis, and normal pulmonary physiology. Cluster B had highly symptomatic asthma despite high step-level treatment, lower allergy and inflammation, and mildly altered pulmonary physiology. Cluster C had minimally symptomatic asthma and rhinitis, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Clusters D and E exhibited progressively higher asthma and rhinitis symptoms and allergy/inflammation. Cluster E had the most symptomatic asthma while receiving high step-level treatment and had the highest total serum IgE level (median, 733 kU/L), blood eosinophil count (median, 400 cells/mm3), and allergen sensitizations (15 of 22 tested). Allergy distinguishes asthma phenotypes in urban children. Severe asthma often coclusters with highly allergic children. However, a symptomatic phenotype with little allergy or allergic inflammation was identified.


"What Smell?" Temporarily Loading Visual Attention Induces a Prolonged Loss of Olfactory Awareness.
The human sense of smell is highly sensitive, often conveying important biological signals. Yet anecdotal evidence suggests that we commonly fail to notice suprathreshold environmental olfactory stimuli. The determinants of olfactory awareness are, as yet, unknown. Here, we adapted the inattentional-blindness paradigm to test whether olfactory awareness is dependent on attention. Across three experiments, participants performed a visual search task with either a high or low perceptual load (a well-established attentional manipulation) while exposed to an ambient coffee aroma. Consistent with our hypothesis, results showed that task load modulated olfactory awareness: 42.5% fewer participants in the high- than in the low-load condition reported noticing the coffee aroma. Our final experiment demonstrates that because of unique characteristics of olfactory habituation, the consequences of inattentional anosmia can persist even once attention becomes available. These findings establish the phenomenon of inattentional anosmia and have applied implications for predicting when people may miss potentially important olfactory information.


The regulation of leucocyte transendothelial migration by endothelial signalling events.
Leucocytes use sophisticated mechanisms to cross the endothelium lining the vasculature. This is initiated by chemokine- and adhesion molecule-induced intracellular signalling that controls adhesion, spreading, and motility. At the same time, adherent leucocytes trigger the endothelium, manipulating the barrier to promote their transmigration into the underlying tissues. Over the past years, our insights in the associated signalling events within the endothelium have increased considerably, albeit the order of events, their crosstalk, and the consequences for endothelial cells and leucocytes are only partially resolved. Here, we briefly review endothelial signalling that is initiated at the apical endothelial membrane, where the first contact with the leucocytes takes place and signal transduction is induced. In addition, we discuss subsequent events at endothelial cell-cell junctions insofar as they have been linked to transendothelial migration. Finally, we briefly touch upon the modulation of endothelial signalling by infectious pathogens, since these have developed additional, elegant ways to manipulate the endothelium and transendothelial migration that may provide new, relevant insights into this process.


B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents.
Patients with rheumatoid arthritis (RA) in whom the response to anti-tumor necrosis factor (anti-TNF) therapy is inadequate have several therapeutic options, such as switching to an alternative anti-TNF agent or initiating B cell-depleting therapy with rituximab (RTX). Although both therapeutic options have been proven effective in trials, no head-to-head comparisons are available. The aim of this study was to compare the effectiveness of RTX with that of an alternative anti-TNF agent in the management of patients with RA who had an inadequate response to anti-TNF therapy. This prospective cohort study was nested within the Swiss Clinical Quality Management RA cohort and included all patients who had an inadequate response to at least 1 anti-TNF agent and subsequently received either 1 cycle of RTX or an alternative anti-TNF agent. The primary outcome was the evolution of RA disease activity (as measured on the Disease Activity Score in 28 joints [DAS28]), which was analyzed using multivariate regression models for longitudinal data. One hundred sixteen patients with RA were included; 50 patients received 1 cycle of RTX, and 66 patients were treated with a second or a third alternative anti-TNF agent. At baseline, there were no significant differences between the 2 groups in age, sex, disease duration, and disease activity. Evolution of the DAS28 was more favorable in the group that received RTX compared with the group that received an alternative anti-TNF agent (P = 0.01). At 6 months, the mean decrease in the DAS28 was -1.61 (95% confidence interval [95% CI] -1.97, -1.25) among patients receiving RTX and -0.98 (95% CI -1.33, -0.62) among those receiving subsequent anti-TNF therapy. The results of this observational study suggest that treatment with RTX may be more effective than switching to an alternative anti-TNF agent in patients with RA in whom active disease persists despite anti-TNF therapy.


Frontline Dasatinib Treatment in a "Real-Life" Cohort of Patients Older than 65 Years with Chronic Myeloid Leukemia.
Dasatinib (DAS) has been licensed for the frontline treatment in chronic myeloid leukemia (CML). However, very few data are available regarding its efficacy and toxicity in elderly patients with CML outside clinical trials. To address this issue, we set out a "real-life" cohort of 65 chronic phase CML patients older than 65 years (median age 75.1 years) treated frontline with DAS in 26 Italian centers from June 2012 to June 2015, focusing our attention on toxicity and efficacy data. One third of patients (20/65: 30.7%) had 3 or more comorbidities and required concomitant therapies; according to Sokal classification, 3 patients (4.6%) were low risk, 39 (60.0%) intermediate risk, and 20 (30.8%) high risk, whereas 3 (4.6%) were not classifiable. DAS starting dose was 100 mg once a day in 54 patients (83.0%), whereas 11 patients (17.0%) received less than 100 mg/day. Grade 3/4 hematologic and extrahematologic toxicities were reported in 8 (12.3%) and 12 (18.5%) patients, respectively. Overall, 10 patients (15.4%) permanently discontinued DAS because of toxicities. Pleural effusions (all WHO grades) occurred in 12 patients (18.5%) and in 5 of them occurred during the first 3 months. DAS treatment induced in 60/65 patients (92.3%) a complete cytogenetic response and in 50/65 (76.9%) also a major molecular response. These findings show that DAS might play an important role in the frontline treatment of CML patients >65 years old, proving efficacy and having a favorable safety profile also in elderly subjects with comorbidities.


Dietary sodium intake and overweight and obesity in children and adults: a protocol for a systematic review and meta-analysis.
Overweight and obesity in children and adults is a major public health concern. Emerging evidence suggests dietary sodium intake may be associated with obesity. This systematic review and meta-analysis will aim to (i) assess the relation between dietary sodium intake and measures of adiposity in children and adults and (ii) examine the relation between sodium intake and sugar-sweetened beverage (SSB) consumption, which is a known risk factor for obesity. An electronic search will be conducted using Medline Complete, CINAHL, Scopus, Embase and Cochrane central register of controlled trials (CENTRAL). The search strategy will identify published peer-reviewed articles that report on dietary sodium and either a marker of adiposity or SSB consumption. Only human studies (ages >1 year) in English will be included, and no limits will be placed on publication date. No restrictions will be placed on the method of sodium intake assessment. Cross-sectional, prospective studies, and randomised controlled trials with a duration of ≥ 3 months will be included. Studies with participants with renal disease, cancer, type 1 diabetes or heart failure or who are pregnant will be excluded. To assess the quality of studies, the Cochrane's Collaboration tool for assessing risk of bias in randomised trials will be used for randomised controlled trials (RCTs), and the modified Newcastle-Ottawa Scale will be used for cross-sectional and prospective studies. Meta-analysis will be used to assess the relation of sodium intake with two primary outcomes: (i) BMI and body weight in adults and BMI z-score in children and (ii) weight category (i.e. healthy weight vs. overweight/obese). For any outcomes in which meta-analysis is not possible, we will present data as a systematic review. Findings will be grouped and reported separately for children and adolescents (ages 1-17 years) and adults (ages >18 years). This review and meta-analysis will provide insight into the relation between dietary sodium intake and overweight and obesity. This information can be used to inform public health policies which target population sodium consumption. Prospero CRD42015016440.


Predicting incident dementia 3-8 years after brief cognitive tests in the UK Biobank prospective study of 500,000 people.
Prospective studies reporting associations between cognitive performance and subsequent incident dementia have been subject to attrition bias. Furthermore, the extent to which established risk factors account for such associations requires further elucidation. We used UK Biobank baseline cognitive data (n ≤ 488,130) and electronically linked hospital inpatient and death records during three- to eight-year follow-up, to estimate risk of total dementia (n = 1051), Alzheimer's disease (n = 352), and vascular dementia (n = 169) according to four brief cognitive tasks, with/without adjustment for constitutional and modifiable risk factors. We found associations of cognitive task performance with all-cause and cause-specific dementia (P < .01); these were not accounted for by established risk factors. Cognitive data added up to 5% to the discriminative accuracy of receiver operating characteristic curve models; areas under the curve ranged from 82% to 86%. This study offers robust evidence that brief cognitive testing could be a valuable addition to dementia prediction models.


Component Microenvironments and System Biogeography Structure Microorganism Distributions in Recirculating Aquaculture and Aquaponic Systems.
Flowthrough and pond aquaculture system microbiome management practices aim to mitigate fish disease and stress. However, the operational success of recirculating aquaculture systems (RAS) depends directly on system microbial community activities. In RAS, each component environment is engineered for a specific microbial niche for waste management, as the water continuously flowing through the system must be processed before returning to the rearing tank. In this study, we compared waste management component microbiomes (rearing tank water, pH correction tank, solid-waste clarifier, biofilter, and degassing tower) within a commercial-scale freshwater RAS by high-throughput 16S rRNA gene sequencing. To assess consistency among freshwater RAS microbiomes, we also compared the microbial community compositions of six aquaculture and aquaponic farms. Community assemblages reflected site and source water relationships, and the presence of a hydroponic subsystem was a major community determinant. In contrast to the facility-specific community composition, some sequence variants, mainly classified into Flavobacterium, Cetobacterium, the family Sphingomonadaceae, and nitrifying guilds of ammonia-oxidizing archaea and Nitrospira, were common across all facilities. The findings of this study suggest that, independently of system design, core taxa exist across RAS rearing similar fish species but that system design informs the individual aquatic microbiome assemblages. Future RAS design would benefit from understanding the roles of these core taxa and then capitalizing on their activities to further reduce system waste/added operational controls.IMPORTANCE Recirculating aquaculture systems (RAS) are agroecosystems for intensive on-land cultivation of products of fisheries. Practitioners that incorporate edible plant production into RAS refer to these facilities as aquaponic systems (AP). RAS have the potential to offset declining production levels of wild global fisheries while reducing waste and product distance to market, but system optimization is needed to reduce costs. Both RAS and AP rely on microbial consortia for maintaining water quality and promoting fish/plant health, but little is known about the microorganisms actually present. This lack of knowledge prevents optimization of designs and operational controls to target the growth of beneficial microbial species or consortia. The significance of our research is in identifying the common microorganisms that inhabit production RAS and AP and the operational factors that influence which microorganisms colonize and become abundant. Identifying these organisms is a first step toward advanced control of microbial activities that improve reproducibility and reduce costs.


Transcriptional Control of Glutaredoxin GRXC9 Expression by a Salicylic Acid-Dependent and NPR1-Independent Pathway in Arabidopsis.
Salicylic acid (SA) is a key hormone that mediates gene transcriptional reprogramming in the context of the defense response to stress. GRXC9, coding for a CC-type glutaredoxin from Arabidopsis, is an SA-responsive gene induced early and transiently by an NPR1-independent pathway. Here, we address the mechanism involved in this SA-dependent pathway, using GRXC9 as a model gene. We first established that GRXC9 expression is induced by UVB exposure through this pathway, validating its activation in a physiological stress condition. GRXC9 promoter analyses indicate that SA controls gene transcription through two activating sequence-1 (as-1)-like elements located in its proximal region. TGA2 and TGA3, but not TGA1, are constitutively bound to this promoter region. Accordingly, the transient recruitment of RNA polymerase II to the GRXC9 promoter, as well as the transient accumulation of gene transcripts detected in SA-treated WT plants, was abolished in a knockout mutant for the TGA class II factors. We conclude that constitutive binding of TGA2 is essential for controlling GRXC9 expression, while binding of TGA3 in a lesser extent contributes to this regulation. Finally, overexpression of GRXC9 indicates that the GRXC9 protein negatively controls its own gene expression, forming part of the complex bound to the as-1-containing promoter region. These findings are integrated in a model that explains how SA controls transcription of GRXC9 in the context of the defense response to stress.


Oil/water separation with selective superantiwetting/superwetting surface materials.
The separation of oil from oily water is an important pursuit because of increasing worldwide oil pollution. Separation by the use of materials with selective oil/water absorption is a relatively recent area of development, yet highly promising. Owing to their selective superantiwetting/superwetting properties towards water and oil, superhydrophobic/superoleophilic surfaces and underwater superoleophobic surfaces have been developed for the separation of oil/water-free mixtures and emulsions. In this Review, after a short introduction to oil/water separation, we describe the principles of materials with selective oil/water absorption and outline recent advances in oil/water separation with superwetting/superantiwetting materials, including their design, their fabrication, and models of experimental setups. Finally, we discuss the current state of this new field and point out the remaining problems and future challenges.


Risk-Taking Behavior and Suicidality: The Unique Role of Adolescent Drug Use.
Research has supported an association between suicidal thoughts/behaviors and risk taking, which may be particularly strong during adolescence when risk taking is known to increase. However, extant research has focused on individual risk-taking behaviors (e.g., alcohol use), limiting our ability to evaluate the unique association between different risk-taking behaviors and suicidal thoughts/behaviors. The current study aimed to fill this gap by examining the simultaneous influence of multiple risk-taking behaviors (i.e., risky sexual behavior, tobacco/alcohol use, illicit drug use, delinquent behavior, violent behavior) on adolescent suicidal thoughts/behaviors. Data from the National Longitudinal Study of Adolescent Health was utilized. The sample consisted of 4,834 adolescents who completed home interviews at two time points. At the first time point, participants' mean age was 15.15, with 48% (n = 2,315) identifying as male. Participants provided information about suicidal thoughts/behaviors and multiple risk-taking behaviors at an initial interview and at a second interview, approximately 11 months later. When independently examined, nearly all assessed risk-taking behaviors were independently associated with suicidal ideation concurrently and prospectively, and with suicide attempts concurrently. When all risk-taking behaviors were examined simultaneously, illicit drug use was the only significant concurrent and significant prospective, albeit negative, predictor of suicidal thoughts and only concurrent predictor of suicidal behavior. The current findings suggest that illicit drug use may have a stronger association with suicidal thoughts and behaviors than other risk-taking behavior. These findings have implications for prevention and intervention programs for adolescents.


[Eosin Y-sensitive ATPase activity in men's spermatozoids as a biochemical test for oligozoospermia].
The experiments performed on preparations of spermatozoids of men of reproductive age (27-44-year old) studied the ATPase activity (sensitive to inhibited effects of eosine Y) in both normal and oligozoospermia conditions when treating cell suspension with detergents. The methodical approaches for testing the so-called "common" and eosin Y-sensitive ATP-hydrolase activities in spermatozoids were developed. Saponin, the optimal detergent for permeabilisation of their plasma membrane was chosen using laser-correlational spectroscopia method. Saponin perforates effectively the membranes of spermatozoids, decreasing the average hydrodynamical diameter of cells from 10-15 microm (the spermatozoids themselves) to 3-8 microm (treating cell suspension with 0.05% solution of saponin) and even to 2-3 microm (treating spermatozoids suspension with 0.5% solution of detergent). A non-specific inhibitor of ATP-hydrolase's systems, eosin Y, decreases effectively the ATP-hydrolase activity of intact spermatozoids up to 40%. The exact effect of eosin depends on composition of incubation medium. In the model of extracellular conditions (the optimal concentration of detergent is 0.05%), eosin Y-sensitive ATP-hydrolase's activity of spermatozoids in both normal and oligozoospermia cases is increased by 220-240% (at an average). If enzymatic reaction was performed during intracellular conditions modeling (the optimal concentration of saponin is 0.5%), the increase of eosin Y-sensitive ATPase activity (up to 350-400% in normal conditions, and only to 130-150% in oligozoospermia conditions) was detected. This specificity can be used as easy-to-use clinical test for such pathology of men's reproductive system. Eosin Y inhibited doze-dependently the common ATPase activity in spermatozoids in both normal and with studied pathology. In both cases, after linearization of curves of catalytic titration of ATPase activity with eosin Y in Hill's plot the two-phase dependency, of high and low affinities, was found (the average values of imaginary inhibition constant I(0,5) are 0.1 and 0.3-0.4 mM correspondingly). In both normal and oligozoospermia conditions, the high-affinity component has a positive cooperativity, while the low-affinity component is characterized by a negative cooperativity. The obtained results may be of both theoretical and practical value for further investigation of membrane mechanisms used in the support of ion homeostasis in men's spermatozoids and its violation in conditions under different pathological states. Besides, the results can be used as a theoretical basis for improvement of simple and accessible clinical biochemical methods used for testing such a pathology as oligozoospermia.


Developmental regulation and partial-length cloning of tubulointerstitial nephritis antigen of murine metanephros.
Tubulointerstitial nephritis antigen (TIN-ag) is an extracellular matrix (ECM) glycoprotein that has been recently isolated and cloned from the rabbit kidney. It is an integral component of the basal lamina, and unlike other basement membrane proteins it is exclusively expressed in the tubular basement membranes (TBMs). Since other ECM glycoproteins have been shown to regulate development of various organ systems, studies were initiated to ascertain its developmental regulation in renal tubulogenesis and glomerulogenesis. Embryonic (day-13 and -17 of gestation), newborn and one-week-old mice kidneys were harvested for expression of TIN-ag as well as cDNA cloning studies. Immunostaining with polyclonal anti-TIN-ag antibody revealed its localization to the basal lamina of ureteric bud branches and epithelial elements of developing nephrons in day-13 embryonic kidneys. Interestingly, it was heavily expressed at the tips of the ureteric bud branches, and was not expressed in the distal convolutions of the S-shaped body stage of the nephrons, the region which forms the future glomerulus. At day-17, TIN-ag expression was less, and the immuno-reactivity was mainly localized to the cortex. In the newborn and one-week-old mice kidneys, the cortical expression of TIN-ag increased progressively, but was absent in the glomeruli. The TIN-ag expression was confined to the cortical TBMs, while absent in the medullary tubules, the latter included segments of the collecting ducts and loop of Henle. Immunoprecipitation studies on [35S]methionine-labeled metanephroi revealed a single band of approximately 58 kDa at day-13, and the incorporated radioactivity decreased at day-17. No high molecular weight isoforms were observed. A partial-length mouse TIN-ag cDNA of approximately 530 bp PCR product was generated, and it had approximately 88% and approximately 93% nucleotide and amino acid sequence homolgy, respectively, with rabbit TIN-ag. Utilizing this cDNA, Northern blot analyses revealed a single transcript of approximately 2 Kb in fetal and postnatal mice kidneys. mRNA expression initially decreased at day-17, and then progressively increased by one week. Utilizing a mouse TIN-ag riboprobe, in situ hybridization studies revealed a generalized diffuse expression of TIN-ag in the epithelial clements of developing nephrons and ureteric bud branches at day-13. Gene expression decreased by day-17, and became confined to the renal cortex, and then progressively increased during the neo- and post-natal periods, but remained absent in the renal medulla and glomeruli. These data indicate that TIN-ag is expressed in the metanephros early in embryonic life in the absence of any detectable isoforms, and it exhibits spatio-temporal characteristics during metanephric development. Being concentrated at the tips of the ureteric bud branches, it is conceivably involved in epithelial:mesenchymal interactions which are highly prevalent during renal organogenesis, and its role in tubulogenesis diverges from glomerulogenesis at the S-shaped body stage of the nephron.


Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.
To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.


Trabeculectomy-related complications in Olmsted County, Minnesota, 1985 through 2010.
Trabeculectomy is the surgical standard of care for patients with medically refractory glaucoma. The use of antimetabolite agents, such as mitomycin, has increased the rate of complications after trabeculectomy. To determine the rate of trabeculectomy-related complications during a 25-year study. For this retrospective, population-based study, we enrolled the residents of Olmsted County, Minnesota, who underwent a trabeculectomy from January 1, 1985, through December 31, 2010, at the Mayo Clinic and Olmsted Community Hospital. Data were collected from August 2012 to September 2013 followed by data analysis through January 2014. After reviewing the patient records, we determined the occurrence of complications, including bleb leak, hypotony, hyphema, choroidal effusion, choroidal hemorrhage, blebitis, and endophthalmitis, as they relate to the mitomycin concentration administered during the operation. We reviewed relevant publications in Ovid, MEDLINE, and PubMed to identify studies representative of the reported trabeculectomy complication rate. Cumulative probabilities of short- and long-term complications, determined using the Kaplan-Meier method, and the relation to mitomycin concentration applied during trabeculectomy. In 334 patients, 460 eyes underwent trabeculectomy (mean [SD; range] follow-up, 7.7 [5.7; 0-27.7] years). Among them, 159 eyes had complications, with early complications (<3 months) in 100 eyes and late complications (≥3 months) in 59 eyes during the follow-up. Ten eyes had an early and a late complication. The 20-year cumulative chances of early, late, or any complication were 19.7% (95% CI, 16.2%-23.6%), 26.0% (95% CI, 15.0%-36.0%), and 45.0% (95% CI, 38.0%-52.0%), respectively. The cumulative probabilities of vision-threatening complications during 20 years were 2.0% (95% CI, 0%-4.0%) for blebitis and 5.0% (95% CI, 1.0%-9.0%) for endophthalmitis. Association between the rate of trabeculectomy complications and mitomycin dose used was P = .77. In total, 98 cases (21.3%) underwent further surgical procedures related directly to the complication. The rate of trabeculectomy-related complications does not appear to be associated with mitomycin use during a mean follow-up of 7.7 years. The rate of vision-threatening complications appears to be comparable to those of previous studies of shorter duration.


Impact of a nurse vaccination program on hepatitis B immunity in a Swiss HIV clinic.
We evaluated the impact of a nurse program for hepatitis B virus vaccination in a center from the Swiss HIV Cohort Study. Immunity (anti-HBs >10 IU/mL) increased from 32% to 76% in the intervention center (n = 238) where vaccine management was endorsed by nurses, but only from 33% to 39% in control centers (n = 2712, P < 0.001) where management remained in charge of physicians. Immunity against HBV in the HIV population is insufficient in Switzerland. Specific nurse vaccination program may efficiently improve health care.


Influence of Body Composition, Oral Contraceptive Use, and Physical Activity on Bone Mineral Density in Premenopausal Women.
In premenopausal women, low bone density may reflect attainment of a lower peak bone mass which can increase risk of osteoporosis after menopause. The purpose of this study was to examine the relationship between total body, lumbar spine, and proximal femur bone mineral density (BMD) and body composition and oral contraceptive (OC) use in 18-30 year old women. Sixty-five healthy women, split into groups of oral contraceptive users (OC, n = 36) and non oral contraceptive users (Non-OC, n = 29), completed Baecke physical activity, calcium intake, and menstrual history questionnaires. Total body, AP lumbar spine, and dual proximal femur scans were performed using Dual Energy X-Ray Absorptiometry (DXA). Body composition measures were obtained from the total body scan analysis. No significant differences were found for BMD in OC users and non-users. Bone free lean body mass (BFLBM) and weight were positively correlated to all BMD sites, and fat mass was related to total body and L1-L4 spine BMD (p < 0.05). Stepwise regression analyses determined that weight was a significant predictor for all BMD sites (p < 0.05). When separating the two components of body weight, BFLBM was a significant predictor for all BMD sites, and fat mass only predicted total body BMD. In conclusion, this study indicates that weight and BFLBM are significant contributors to BMD in young healthy premenopausal women, and OC use did not influence the relationship between BMD and BFLBM.


[Physiology of the growth and supersynthesis of DNA-polymerase in Escherichia coli during 2-stage continuous cultivation].
The physiology of growth under the conditions of batch and continuous cultivation was studied with the recombinant strain of Escherichia coli CM 5199 capable of DNA polymerase I superproduction. The specific growth rate of the strain is 0.8 h-1 under the conditions of continuous cultivation which is almost 2.5 times greater than that in the exponential phase of batch cultivation. When the strain was cultivated at a flow rate above 0.3 h-1, the biomass concentration in the fermenter decreased and the culture was no more limited by the carbon source in the absence of other growth limiting components of the medium. Apparently, the metabolic product ceased to inhibit high growth rates of the culture under the conditions of continuous cultivation. The rate of DNA polymerase synthesis correlated with the specific growth rate and the respiration activity of the culture when the lambda pol A prophage was induced in the cells. The authors discuss the effectiveness of ribosome operation in the cells at a growth rate of 0.05 to 0.3 h-1 and the content of ribosomes at a higher growth rate in relation to DNA polymerase I synthesis.


Elements of effective community engagement: lessons from a targeted malaria elimination study in Lao PDR (Laos).
Mass drug (antimalarial) administration (MDA) is currently under study in Southeast Asia as part of a package of interventions referred to as targeted malaria elimination (TME). This intervention relies on effective community engagement that promotes uptake and adherence in target communities (above 80%). Based on the experienced of designing and implementing the community engagement for TME in Laos, in this article we aim to present the elements of effective community engagement for mass antimalarial administration. The design and implementation of community engagement, which took place from September 2015 to August 2016 was recorded as field notes, meeting minutes and photographs. These data underwent qualitative content analysis. The community engagement strategy that accompanied TME in Laos was successful in terms of contributing to high levels of participation in mass anti-malarial administration (above 85%). Based on the experience of designing and implementing the community engagement, five key elements were identified: (1) stakeholder and authority engagement, which proceeded from national level, to regional/district and local level; (2) local human resources, particularly the recruitment of local volunteers who were integral to the design and implementation of activities in the study villages; (3) formative research, to rapidly gain insight into the local social and economic context; (4) responsiveness whereby the approach was adapted according to the needs of the community and their responses to the various study components; and (5) sharing control/leadership with the community in terms of decisions on the organization of TME activities. The community engagement that accompanied TME in Laos had to deal with challenges of implementing a complex study in remote and linguistically isolated villages. Despite these challenges, the study recorded high population coverage. Lessons learnt from this experience are useful for studies and intervention programs in diverse contexts.